Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety. Full citations for publications not cited fully within the specification are set forth at the end of the specification.
The diverse roles played by the immune system in cancer initiation and development are illustrated by two concepts: the “cancer immunoediting” theory, which postulates that the immune system protects the host against cancer development (Dunn et al., 2002, Nature Immunol. 3:991-998; Swann et al., 2007, J. Clin. Invest. 117:1137-1146) and the traditional concept that long-lasting inflammatory reactions facilitate malignant transformation and cancer progression (Coussens et al., 2002, Nature 420:860; Balkwill et al., 2001, Lancet 357:539-545; Bhardwaj et al., 2007, J. Clin. Invest. 117:1130-1136; Lin et al., 2007, J. Clin. Invest. 117:1175-1183; Blank et al., 2004, Cancer Res. 64:1140). Although an immune reaction develops against malignant tumor cells, tumors have the capacity to suppress this immune response, escaping from immune effector mechanisms (Swann et al., 2007, J. Clin. Invest. 117:1137; Blank et al., 2004, Cancer Res. 64:1140-1145; Dong et al., 2002, Nature Med. 8:793-800). Antigen-specific CD8+ T cell tolerance, induced by myeloid-derived suppressor cells (MDSCs) recruited by tumors, is an example of one such suppression mechanism (Sica et al., 2007, J. Clin. Invest. 117:1155-1166; Kusmartsev et al., 2005, J. Immunol. 175:4583-4592). Although mechanisms responsible for the suppressive phenotype of MDSCs vary, several studies postulate that MDSCs produce large quantities of reactive oxygen or nitrogen species (ROS or RNS, respectively), which directly inhibit the antigen-specific CD8+ T cell-dependent immune response (Kusmartsev et al., 2004, J. Immunol. 172:989-999). In addition, L-arginine metabolism regulated by arginase-1 contributes to the generation of these reactive species and seems to have a central role for the suppression of T cells by MDSCs (Marx et al., 2008, Science 319:154-156). The immunosuppressive capacity of MDSCs is thought to be one of the major obstacles limiting the use of anti-cancer vaccines (Bhardwaj, 2007, J. Clin. Invest. 117:1130-1136).
Another potential player in the response to cancer is the complement system, which has an essential role in inflammation and the innate immune response against infections (Markiewski et al., 2007, Am. J. Pathol. 171:715-727). Complement's wide-ranging activities link the innate immune response to the subsequent activation of adaptive immunity (Carroll, 2004, Nature Immunol. 5:981-986). Circulating complement proteins are activated by limited proteolysis occurring on the surface of pathogens or modified host cells. Some of the resulting cleavage products are deposited on pathogen or host cell surfaces, and others are released into body fluids, where they interact with specific receptors on various target cells. Of these complement components, the C3 protein is considered to be central to the complement cascade. Enzymatic cleavage of C3 leads to the production of the anaphylatoxin C3a, an inflammatory mediator and chemoattractant, and C3b (Sahu et al., 1998, Immunol. Res. 17:109-121). C3b plays a role in the opsonization and subsequent clearance of pathogens, but is also a main component of the C5 convertase, an enzyme complex that cleaves C5 to produce the anaphylatoxin C5a and C5b. The ensuing cell-surface deposition of the C5b fragment contributes to the formation of the pore-like membrane attack complex (MAC) within cellular membranes, whereas C5a is released and acts as an even more potent chemoattractant and inflammatory mediator than C3a (Markiewski et al., 2007, Am. J. Pathol. 171:715-727; Guo et al., 2005, Ann. Rev. Immunol. 23:821-852).
Formation of the MAC leads to the lysis of bacteria or other foreign cells and, under certain pathophysiological conditions, lysis of host cells, as well (Markiewski et al., 2007, Am. J. Pathol. 171:715-727). Given that several complement components have been found to be deposited in the tumor tissue of patients, the MAC was originally thought to contribute to the immunosurveillance of malignant tumors by complement (Fishelson et al., 2003, Mol. Immunol. 40:109-123; Donin et al., 2003, Clin. Exp. Immunol. 131:254-263). Further studies revealed, however, that malignant tumor cells are protected against such complement-mediated lysis because they overexpress complement regulators that limit complement activation and deposition in situ, and, therefore, the formation of the MAC (Fishelson et al., 2003, Mol. Immunol. 40:109-123; Donin et al., 2003, Clin. Exp. Immunol. 131:254-263). It has recently been postulated that the ability of the MAC to lyse foreign and host cells might enhance the efficacy of cancer immunotherapies involving monoclonal antibodies specific for particular tumor antigens, since complement proteins enhance antibody-dependent cytotoxicity (Macor et al., 2007, Immunol. Lett. 111:6-13; Gelderman et al., 2004, Trends Immunol. 25:158-164).
Despite investigation into the anti-cancer potential of the complement system, a distinctly different role for complement effectors as factors that might promote tumor growth has not yet been explored.